The present invention relates to 5-(optionally substituted phenyl)-6H-1,3,4-thiadiazin-2-amines, having activity as muscle relaxants.
As a general class, 5-(optionally substituted phenyl)-6H-1,3,4-thiadiazine-2-amines are known as chemical intermediates. See, for example, Japanese Pat. Nos. 74-110,696, 74-110,697 and 74-100,080. Many individual species within the scope of the compounds defined herein and also species related thereto are also known as chemical intermediates. See, for example:
1. Japanese Pat. No. 75 37651; PA1 2. McLean et al., J. Chem. Soc. 1937, 556-9; PA1 3. Avramovici, Analele stiint. univ. "Al. I. Cuza" lasi, Sect. 1 (Mat. Fiz., chim.). (N.S.) 1, 315-319 (1955). CA51:10541; PA1 4. Beyer et al., Justus Liebigs Ann. Chem. 741, 45-54 (1970); PA1 5. Japanese Pat. No. 74-110,696; PA1 6. Japanese Pat. No. 74-110,697; PA1 7. Bose, Quart. J. Indian Chem. Soc. 1, 51-62 (1924), PA1 8. Beyer et al., Chem. Ber. 89, 107-14 (1956); PA1 9. Japanese Pat. No. 74-88889; PA1 10. Japanese Pat. No. 74-100,080; PA1 11. Bose, Quart. J. Ind. Chem. Soc. 2, 95-114 (1925); PA1 12. Bose et al., J. Indian Chem. Soc. 7, 733-9 (1930); PA1 13. Bulka et al., Z. Chem. 15(12), 482 (1965); PA1 14. Schmidt et al., Tetrahedron Lett. 1975 (1), 33-6; PA1 15. Beyer, Quart, Rep. Sulfur Chem. 5(3), 177-89 (1970); PA1 16. Saraswathi et al., Indian J. Chem. 10(12), 1151-4 (1972); PA1 17. Hampel, Z. Chem. 9(2), 61-2 (1969); PA1 18. Pfeiffer et al., Z. Chem. 17(6), 218-20 (1977); PA1 19. Pfeiffer et al., Synthesis 1977(7), 485-6; and PA1 20. Pfeiffer et al., Synthesis 1977(3), 196-8. Certain species are further known as flame retardants (Japanese Pat. No. 74-5439). PA1 R.sub.1 is H, C.sub.1-7 straight or branched chain alkyl, allyl or phenyl; PA1 R.sub.2 is phenyl, phenyl monosubstituted with F, Cl, C.sub.1-4 straight or branched chain alkyl or phenyl disubstituted in the 2- and 4-positions with Cl or C.sub.1-4 straight or branched chain alkyl; and PA1 R.sub.3 is H or C.sub.1-4 straight or branched chain alkyl, with the proviso that when R.sub.3 is straight or branched chain alkyl, R.sub.2 is unsubstituted phenyl; PA1 or a pharmaceutically acceptable acid addition salt thereof.
Moreover, some 2-amino-1,3,4-thiadiazines are generally known to have antiviral, anti-inflamatory and analgesic activity (Japanese Pat. No. 74-88889). Additionally, many individual species within the scope of those defined herein, as well as others related in structure are disclosed in this same reference. Some species have been found ineffective as vitamin B substitutes (Robbins et al., Proc. Natl. Acad. Sci. U.S. 24, 141-5 (1938) and anti-tubercular agents (Ban., J. Pharm. Soc. Japan 73, 533-7 (1953) and Bilinski et al., Bull. Acad. Polon, Sci., Ser. Sci. Chim. 13(6), 393-6 (1965)).
Other compounds having significantly different structures are also known to possess pharmacological activity.
4-Methyl-4H-5,6-dihydro-1,3,4-thiadiazin-2-amines are known to be CNS active (U.S. Pat. No. 3,428,631 and Trepanier et al., J. Med. Chem. 10(6), 1085-7 (1967)). Additionally, 3-substituted-1,2-dihydro-1,3,4-thiadiazin-2-imines are known as slow cure accelerators for rubber (U.S. Pat. No. 2,871,237).
The 5-membered ring-containing 2-amino-1,3,4-thiadiazoles are known to possess CNS depressant activity (Maffii et al., Il Farmaco (Pavia) Ed. Sci. 13, 187-217 (1958); Great Britain Pat. No. 815,188; West German Pat. No. 2,212,245 (or Great Britain Pat. No. 1,380,136); U.S. Pat. No. 3,965,110; U.S. Pat. No. 4,054,665; U.S. Pat. No. 3,919,428; and U.S. Pat. No. 3,992,396) and antihypertensive activity (U.S. Pat. No. 3,746,716).
These 5-membered ring-containing 1,3,4-thiadiazole-2-amines are a class of compounds treated by the prior art as distinct from the 6-membered ring-containing 1,3,4-thiadiazin-2-amines. However, the preparation of both types of compounds are reported together by Rao, Khim. Geterotsikl. Soedin. 1977(3), 291-310, as does Klosa, Arch. Pharm. 287, 12-14 (1954). In the latter reference, the compounds are reported as potential, but untested, tuberculostatics. Compounds of both types are also disclosed in Japanese Pat. No. 74 5439 as fire retardants.